Mitochondrial citrate metabolism and efflux regulates trophoblast differentiation
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ABSTRACT:
PROVIDER: PRJNA926624 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23194000_1.fastq.gz | Fastqsanger.gz | |||
| SRR23194000_2.fastq.gz | Fastqsanger.gz | |||
| SRR23194001_1.fastq.gz | Fastqsanger.gz | |||
| SRR23194001_2.fastq.gz | Fastqsanger.gz | |||
| SRR23194002_1.fastq.gz | Fastqsanger.gz |
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Project description:Cytotrophoblasts fuse to form and renew syncytiotrophoblasts necessary to maintain placental health throughout gestation. During cytotrophoblast to syncytiotrophoblast differentiation, cells undergo regulated metabolic and transcriptional reprogramming. Mitochondria play a critical role in differentiation events in cellular systems, thus we hypothesized that mitochondrial metabolism played a central role in trophoblast differentiation. In this work, we employed static and stable isotope tracing untargeted metabolomics methods together with gene expression and histone acetylation studies in an established cell culture model of trophoblast differentiation. Trophoblast differentiation was associated with increased abundance of the TCA cycle intermediates citrate and α-ketoglutarate. Citrate was preferentially exported from mitochondria in the undifferentiated state but was retained to a larger extent within mitochondria upon differentiation. Correspondingly, differentiation was associated with decreased expression of the mitochondrial citrate transporter (CIC). CRISPR/Cas9 disruption of the mitochondrial citrate carrier showed that CIC is required for biochemical differentiation of trophoblast. Loss of CIC resulted in broad alterations in gene expression and histone acetylation. These gene expression changes were partially rescued through acetate supplementation. Taken together, these results highlight a central role for mitochondrial citrate metabolism in the orchestration of histone acetylation and gene expression during trophoblast differentiation.
2023-05-05 | GSE223514 | GEO
Project description:Slc25a1 encodes for the mitochondrial citrate carrier, a mitochondrial inner membrane transporter that mediates mitochondrial citrate export. Systemic deletion of Slc25a1 (both homozygous and heterozygous loss) leads to cardiac structural defects and mitochondrial dysfunction. Transcriptomic profiles of metabolic gene expression in the the developing mouse heart at E17.5 reveal alterations in metabolic pathways including oxdiative phosphorylation, supporting mitochondrial structural and functional defects observed with loss of this transporter.
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Project description:TLR activation induces inflammatory responses in macrophages by activating temporally defined transcriptional cascades within the first hours after stimulation. Whether concurrent changes in the cellular metabolism that occur upon TLR activation influence the quality of the transcriptional responses remain unknown. Here we investigated how macrophages adopt their metabolism early after activation to regulate TLR-inducible gene induction. Macrophages increase glucose metabolism and adopt fluxes through the TCA cycle to foster Citrate synthesis. We concomitantly observe activation of ATP-Citrate Lyase (Acly), resulting in augmented acetyl-CoA synthesis and histone acetylation. To investigate which genes and genes classes require ATP-citrate lyase activity for induction we stimulated bone marrow derived macrophages with LPS after ATP-citrate lyase inhibition.
2019-12-16 | GSE129497 | GEO
Project description:Mitochondrial fatty acid synthesis coordinates mitochondrial oxidative metabolism
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Project description:Objective Improving mitochondrial function is a promising strategy for intervention in type 2 diabetes mellitus. This study investigated the preventive effects of sodium ferrous citrate (SFC) and 5-aminolevulinic acid phosphate (ALA) on several metabolic dysfunctions associated with obesity because they have been shown to alleviate abnormal glucose metabolism in humans. Methods Six-week-old male C57BL/6J mice were fed with a normal diet, a high-fat diet, or a high-fat diet supplemented with SFC and ALA for 15 weeks. Results The simultaneous supplementation of SFC + ALA to high-fat diet-fed mice prevented loss of muscle mass, improved muscle strength, and reduced obesity and insulin resistance. SFC + ALA prevented abnormalities in mitochondrial morphology and reverted the diet effect on the skeletal muscle transcriptome, including the expression of glucose uptake and mitochondrial oxidative phosphorylation-related genes. In addition, SFC + ALA prevented the decline in mitochondrial DNA copy number by enhancing mitochondrial DNA maintenance and antioxidant transcription activity, both of which are impaired in high-fat diet-fed mice during long-term fasting. Conclusions These findings suggest that SFC + ALA supplementation exerts its preventive effects in type 2 diabetes mellitus via improved skeletal muscle and mitochondrial health, further validating its application as a promising strategy for the prevention of obesity-induced metabolic disorders.
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Project description:Autophagy is a cellular and energy homeostatic mechanism that contributes to maintain the number of primordial follicles, germ cell survival, and anti-ovarian aging. However, it remains unknown whether autophagy in granulosa cells affects the oocyte maturation. Here, we show a clear tendency of reduced autophagy level in human granulosa cell from women of advanced maternal age, implying a potential negative correlation between autophagy level and oocyte quality. We therefore established a co-culture system and show that either pharmacological inhibition or genetic ablation of autophagy in granulosa cells negatively affect the oocyte quality and fertilization ability. Moreover, our metabolomics analysis indicates that the adverse impact of autophagy impairment on oocyte quality is mediated by downregulated citrate levels, while exogenous supplementation of citrate can significantly restore the oocyte maturation. In molecular level, we found ATP citrate lyase (Acly), which is a crucial enzyme catalyzing the cleavage of citrate, was preferentially associated with K63-linked ubiquitin chains and recognized by the autophagy receptor protein SQSTM1/p62 for the selective autophagic degradation. In human follicles, autophagy levels in granulosa cells was downregulated with maternal aging, accompanied by decreased citrate in the follicular fluid, implying a potential correlation between citrate metabolism and oocyte quality. We also show that elevated citrate levels in porcine follicular fluid promote oocyte maturation. Collectively, our data reveal that autophagy in granulosa cells is a beneficial mechanism to maintain a certain degree of citrate by selectively targeting Acly during oocyte maturation.
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Project description:We report that upon ageing MSC exhibit reduced metabolic rates, with lower lipid biosynthesis and elevated acetyl-CoA levels. However, aged cells display chromatin compaction and histone hypo-acetylation, particularly on enhancers of genes involved in osteogenesis. This is due to the lower levels of citrate carrier, resulting in impaired acetyl-CoA export from mitochondria to the cytosol, which concomitantly affects histone acetylation and osteogenesis. CiC gets degraded in the aged cells via an MVD-lysosomal pathway, which establishes a strong connection between mitochondrial quality control, chromatin and stemness.
2021-07-08 | GSE173358 | GEO
Project description:We report that upon ageing MSC exhibit reduced metabolic rates, with lower lipid biosynthesis and elevated acetyl-CoA levels. However, aged cells display chromatin compaction and histone hypo-acetylation, particularly on enhancers of genes involved in osteogenesis. This is due to the lower levels of citrate carrier, resulting in impaired acetyl-CoA export from mitochondria to the cytosol, which concomitantly affects histone acetylation and osteogenesis. CiC gets degraded in the aged cells via an MVD-lysosomal pathway, which establishes a strong connection between mitochondrial quality control, chromatin and stemness.
2021-07-08 | GSE155714 | GEO
Project description:Aging is the progressive decline in organismal function that leads to an increased risk of multiple diseases and mortality. The molecular basis of this decline is unknown. Using quantitative PCR for mitochondrial mRNA from multiple tissues from the same animals, we found that the rate of change in mouse mitochondrial expression is tissue-specific, with cardiac expression declining early (8-10 months), adipose expression declining late (25-30 months), and no change in kidney or skin. In cardiac tissue, mitochondria-derived mRNA levels declined more slowly than nuclear encoded mRNAs, suggesting a potential dysregulation. These changes were independent of alteration in mitochondrial number, as measured by quantitative PCR of mitochondrial DNA and citrate synthase activity. We found no change in the variability between mitochondrial mRNA levels with age, suggesting that the changes are not due to random dysregulation at the level of gene expression. Caloric restriction (CR), a lifespan-extending intervention proposed to act through mitochondrial biogenesis, delayed the decline in both cardiac and adipose mitochondrial mRNA levels of F344 rats. CR caused an increase in citrate synthase activity but did not alter mitochondrial DNA content, indicating increased translation or reduced turnover of mitochondrial proteins. These results demonstrate that mitochondrial gene expression changes with age are not coupled to mitochondrial number, are likely to be regulated, and are governed by tissue-specific processes. These findings indicate that aging is neither a programmed organism-wide change orchestrated in a top-down fashion nor a product of random dysregulation of gene expression but that tissue-specific factors may independently control aging in different organ compartments. Keywords: aging Cardiac ventricle total RNA from 10 young (4-6 month) and 10 young (25-28 month) mice were compared.
2015-07-03 | E-GEOD-12480 | biostudies-arrayexpress